Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability

İşeri, Sibel Aylin Uğur; Yücesan, Emrah; Tuncer, Feyza Nur; Çalık, Mustafa; Kesim, Yeşim; Uzun, Güneş Altıokka; Özbek, Uğur

doi:10.1038/s10038-019-0570-z

Cited by 13 publications

(7 citation statements)

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“…eEF1 is a multisubunit complex, and genetic mutations of these subunits are causatively linked to neurodevelopmental disorders and ASD (McLachlan et al , 2019). So far, several animal models of eEF1A2 and other eEF1 subunits have been generated and studied, and most of them recapitulate the clinical phenotype (Davies et al , 2017; Ugur Iseri et al , 2019; Larcher et al , 2020). Evidence from human has shown a similar association of eEF2 to neurodevelopmental disorders (Hekman et al , 2012; Hawer et al , 2020; Nabais Sá et al , 2021), strengthening the importance of mRNA translation elongation in brain development.…”

Section: Discussionmentioning

confidence: 99%

eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior

et al. 2022

EMBO Reports

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Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus‐dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR‐mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF‐4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR‐mediated synaptic transmission underlying social novelty behavior.

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Section: Discussionmentioning

confidence: 99%

eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior

et al. 2022

EMBO Reports

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“…While the two variants reported by Reuter and Ugur Iseri et al are loss‐of‐function variants that affect the alternatively spliced exon of eEF1BδL, this is the first study reporting homozygous variants in the highly conserved C‐terminal GEF domain in association with a severe neurodevelopmental disorder 5,6 …”

Section: Discussionmentioning

confidence: 77%

“…Ugur Iseri et al proposed that an altered heat shock transcriptional response ‐ rather than a dysfunctional protein elongation ‐ might be the underlying disease mechanism of the EEF1D ‐associated neurodevelopmental disorders 6 . In cell culture, the overexpression of either wildtype, Lys646Ala or Lys646Arg mutant eEF1BδL upregulated the transcription of heat‐shock element (HSE)‐containing genes 4 .…”

Section: Discussionmentioning

confidence: 99%

“…In a large study on recessive ID, Reuter et al identified homozygous, truncating variants in EEF1D (NM_001130053:c.69delG; p.([Glu24Serfs*26])) in three siblings with severe ID and microcephaly 5 . Recently, Ugur Iseri et al reported the second family with three sisters presenting with ID caused by biallelic truncating variants in EEF1D (NM_001130053:c.948G>A; p.([Trp316*])) 6 . Both reported variants are localized in the alternatively spliced exon that is only retained in the long isoform.…”

Section: Introductionmentioning

confidence: 99%

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Expanding the spectrum of EEF1D neurodevelopmental disorders: Biallelic variants in the guanine exchange domain

et al. 2023

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Protein translation is an essential cellular process and dysfunctional protein translation causes various neurodevelopmental disorders. The eukaryotic translation elongation factor 1A (eEF1A) delivers aminoacyl-tRNA to the ribosome, while the eEF1B complex acts as a guanine exchange factor (GEF) of GTP for GDP indirectly catalyzing the release of eEF1A from the ribosome. The gene EEF1D encodes the eEF1Bδ subunit of the eEF1B complex. EEF1D is alternatively spliced giving rise to one long and three short isoforms. Two different homozygous, truncating variants in EEF1D had been associated with severe intellectual disability and microcephaly in two families. The published variants only affect the long isoform of EEF1D that acts as a transcription factor of heat shock element proteins. By exome sequencing, we Luisa Averdunk and Khalid Al-Thihli contributing equally as first authors and Almundher Al-Maawali and Dagmar Wieczorek as senior authors.

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“…In today's reality, where next generation sequencing (NGS) techniques seem to be the gold standard for disease gene identification, linkage analysis still has a role to serve: Linkage analysis pinpoints candidate chromosomal regions as localization filters for NGS data analysis. In this way, instead of evaluating a large number of samples and variants with unknown significance, a limited number of patients with targeted variants can be examined (6,7). Whole exome sequencing (WES) is a popular tool among all NGS approaches because of its relatively low variant content and easy to handle analysis features compared to whole genome applications (8).…”

Section: Introductionmentioning

confidence: 99%

Combined Analysis of Linkage and Whole Exome Sequencing Reveals Cic as a Candidate Gene for Isolated Dystonia

Salman¹,

Yücesan²,

Samancı³

et al. 2021

jmed

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Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability

Cited by 13 publications

References 24 publications

eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior

eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior

Expanding the spectrum of EEF1D neurodevelopmental disorders: Biallelic variants in the guanine exchange domain

Combined Analysis of Linkage and Whole Exome Sequencing Reveals Cic as a Candidate Gene for Isolated Dystonia

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